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This multi-cohort phase I study is designed to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of oxytocin and to evaluate epelsiban (GSK557296) potential to reduce subendometrial contractractility induced by oxytocin in healthy female subjects. Additionally tissues concentrations of epelsiban will be determined from endometrial tissue biopsies. Data from this study will inform the identification of the doses of epelsiban to be used in future in-vitro fertilization (IVF) clinical studies. Expected number of subjects to be randomized are: Cohort 1- 10 subjects, Cohort 2a- 10 subjects for each epelsiban arm 25 milligrams (mg), 200mg, 5 for placebo, Cohort 2b- 10 subjects per arm with dose to be determined, cohort 3- 6 subjects. Cohorts 1 and 2 will be double blind (sponsor unblinded) placebo controlled cohorts. Cohort 3 will be an open label cohort, cohort 4 will be a double blind (sponsor unblinded) placebo controlled cohort.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Oxytocin or Placebo challenge (Cohort 1) | Experimental | Subjects will receive oxytocin and or placebo challenges as escalating intravenous (IV) infusions administered on the day of ovulation, followed by an IV bolus day 1 post ovulation, and an intramuscular (IM) injection day 2 post ovulation. The planed doses and routes of administration of oxytocin are as follows: IV infusion will be initiated at 5 milliunit/minute (mU/min) and maintained for 60 min, then the rate will be increased to 10 mU/min and maintained for 60 minutes, a final escalation to 20mU/min will be maintained for 60 minutes, after which the infusion will be stopped. For the IV bolus, a single 5 International unit (IU) IV bolus will be administered. For the IM dosing, a single 10 IU IM injection will be administered. |
|
| Epelsiban or Placebo (Cohort 2) | Experimental | Subjects in Cohort 2A will receive first dose of epelsiban (25mg) or placebo after receiving initial oxytocin challenge with dose selected in Cohort 1 followed by 30 minutes washout period. Subjects will receive second dose of epelsiban (150mg) or placebo 12 hours after first dose. Based on the results of Cohort 2A, additional doses may be investigated with a new Cohort 2B (<150mg) and Cohort 2C (>200mg) with repeated oxytocin challenges. |
|
| Biopsy cohort (Cohort 3) | Experimental | Subjects will receive first dose of epelsiban 150mg without oxytocin challenge followed by second dose of epelsiban 150mg 24 hours after the first dose. Subsequently one hour after the second dose, subjects will undergo endometrial biopsies. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Epelsiban | Drug | White to off white Oral tablets with unit dose strength of 5 mg or 25 mg for dose level of 25 mg, 150mg or >150mg |
|
| Measure | Description | Time Frame |
|---|---|---|
| The effect of the infused oxytocin dose on the time course of the frequency of endometrial contractions in Cohort 1 during the periovulatory phase | The relationship between the dose of the infused oxytocin and the time course of the frequency of endometrial contractions in Cohort 1 during the periovulatory phase (ovulation to 3-5 days post ovulation) will be assessed to establish the PD response from the oxytocin infusions and endometrial contraction rate which will provide the oxytocin infusion challenge dose to use in Cohort 2. If data permit, the effective dose 50 (ED50) of oxytocin will be also be determined. Uterine contraction rates, contractility measures, etc. will be measured by computer assisted ultrasound image analyses. | Up to Day 3 |
| Frequency of endometrial contractions in Cohorts 2A, 2B and 2C during the periovulatory phase and 3-5 days post ovulation. | Frequency of endometrial contractions will be assessed to evaluate the dose response relationship for epelsiban with respect to its ability to reduce endometrial contractions in the study population exposed to repeated oxytocin challenges. Uterine contraction rates, contractility measures, etc. will be measured by computer assisted ultrasound image analyses. | Up to Day 2 |
| Reduction in the frequency of subendometrial contractions in Cohorts 2 A, B and C, all during the periovulatory phase. | The reduction in the frequency of subendometrial contractions will be assessed during the periovulatory phase to investigate the PD response of epelsiban in the study population when exposed to repeated oxytocin challenges. If data permit, the infectious dose 50 (ID50) of epelsiban will also be determined. Uterine contraction rates, contractility measures, etc. will be measured by computer assisted ultrasound image analyses. | Up to Day 2 |
| The duration of the reduction in subendometrial contractions in Cohorts 2 A, B and C, all during the periovulatory phase | The duration of the reduction in subendometrial contractions will be assessed during the periovulatory phase to investigate the PD response of epelsiban in the study population when exposed to repeated oxytocin challenges. If data permit, the infectious dose 50 (ID50) of epelsiban will also be determined. Uterine contraction rates, contractility measures, etc. will be measured by computer assisted ultrasound image analyses. |
| Measure | Description | Time Frame |
|---|---|---|
| Frequency of endometrial and subendometrial contractility in Cohort 2. | Following parameters will be assessed: Wave period, external contractile measure, internal contractile measure and total contractile measure, wave directionality, wave amplitude and wave completeness. | Up to Day 3 |
| Frequency of subendometrial contractility in Cohort 3 |
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Inclusion Criteria:
For ultrasound training cohort
For Cohorts 1, 2A, 2B, 2C, 3
Exclusion Criteria:
For Training Cohort
Criteria Based Upon Diagnostic Assessments For Training Cohort
Criteria Based Upon Diagnostic Assessments For Cohorts 1, 2, 3
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| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Glendale | California | 91206 | United States | ||
| GSK Investigational Site |
Not provided
| Label | URL |
|---|---|
| Results for study 116828 can be found on the GSK Clinical Study Register. | View source |
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| ID | Term |
|---|---|
| C571185 | epelsiban |
| D010121 | Oxytocin |
| ID | Term |
|---|---|
| D010909 | Pituitary Hormones, Posterior |
| D010907 | Pituitary Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
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| Placebo | Drug | White to off white oral placebo tablets to match 5mg epelsiban |
|
| Oxytocin | Drug | Oxytocin for IV infusion (at doses of 5, 10, and 20 milliunits), IV bolus (5 IU administered IV as a bolus over 15 seconds) and IM (5 IU administered IM). |
|
| Ortho-Cylcen (21)® tablet | Drug | White, blue or green tablets for oral administration per product insert to synchronize the menstrual cycles with ovulation. Ortho Cyclen (21) ® is a registered trademark of Johnson & Johnson |
|
| Up to Day 2 |
| Plasma concentrations of epelsiban or metabolite and the reduction of subendometrial contraction frequency in Cohorts 2 A, B and C, all during the periovulatory phase. | The relationship between the plasma concentrations and the reduction of subendometrial contraction frequency will be assessed during the periovulatory phase to establish the PK/PD relationship between epelsiban (and/or its metabolites) and endometrial contraction rate in the study population exposed to repeated oxytocin challenges. If data permit, the maximum inhibitory effect (Imax) and IC50 of epelsiban will also be determined. Uterine contraction rates, contractility measures, etc. will be measured by computer assisted ultrasound image analyses. | PK samples will be collected at 3, 3.25, 3.5, 4, 6.5, 11, 15, 27, 31 and 39 hours post dose in cohort 2. |
To evaluate the endometrial and subendometrial contractions following epelsiban dose in the absence of oxytocin challenges. |
| Up to Day 2 |
| Number of subjects with adverse events in Cohort 1 | AEs will be collected from the start of Study Treatment and until the follow-up contact. | 18 days |
| Number of subjects with adverse events (AEs) in Cohort 2 | AEs will be collected from the start of Study Treatment and until the follow-up contact. | 17 days |
| Number of subjects with adverse events in Cohort 3 | AEs will be collected from the start of Study Treatment and until the follow-up contact. | 16 days |
| Change from Baseline in laboratory parameters in Cohort 1 | Laboratory parameters include: hematology, clinical chemistry, urinalysis | Baseline (screening) and upto 21 days |
| Change from Baseline in laboratory parameters in Cohort 2 | Laboratory parameters include: hematology, clinical chemistry, urinalysis | Baseline (screening) and upto 20 days |
| Change from Baseline in laboratory parameters Cohort 3 | Laboratory parameters include: hematology, clinical chemistry, urinalysis | Baseline (screening) and upto 19 days |
| Change from Baseline in vital signs in Cohort 1 | Vital signs measurement include: blood pressure, pulse pressure, heart rate. | Baseline (screening) and upto 21 days |
| Change from Baseline in vital signs in Cohort 2 | Vital signs measurement include: blood pressure, pulse pressure, heart rate. | Baseline (screening) and upto 20 days |
| Change from Baseline in vital signs in Cohort 3 | Vital signs measurement include: blood pressure, pulse pressure, heart rate. | Baseline (screening) and upto 19 days |
| Change from Baseline in electrocardiogram (ECG) parameters in Cohort 1 | ECG parameters include: PR, QRS, QT, and corrected QT (QTc) intervals. | Baseline (screening) and upto 21 days |
| Change from Baseline in ECG parameters in Cohort 2 | ECG parameters include: PR, QRS, QT, and corrected QT (QTc) intervals. | Baseline (screening) and upto 20 days |
| Change from Baseline in ECG parameters in Cohort 3 | ECG parameters include: PR, QRS, QT, and corrected QT (QTc) intervals. | Baseline (screening) and upto 19 days |
| Composite of PK parameters following epelsiban dosing | PK parameters will be assessed for epelsiban and its metabolite (GSK2395448). PK parameters include: maximum plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-time curve (AUC), apparent terminal phase half-life (t1/2), renal clearance (CL). | PK samples will be collected at 3, 3.25, 3.5, 4, 6.5, 11, 15, 27, 31 and 39 hours post dose in cohort 2. |
| Baltimore |
| Maryland |
| 21225 |
| United States |
| D006730 |
| Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |